Oral squamous cell carcinoma (oral SCC) is an aggressive epithelial malignancy that is the 6th most common neoplasm in the world today. Early detection of premalignant lesions in epithelial cells is crucial in order to reduce the mortality rate of 50% which has not changed in several decades. A premalignant lesion caused by carcinogen/smoking appears as a white lesion referred to as "leukoplakia". Frequently this lesion is large (frequently 4-5 cm in diameter) and thus excisional biopsy is not feasible. In contrast, incisional biopsy samples (biopsy of part of the lesion) may not be representative of the entire lesion. Thus, it would be of great value to develop a tool that can be used to discriminate lesions which become malignant from those that remain innocuous. The non-receptor protein tyrosine kinase BRK/Sik is an epithelial cell specific kinase that is involved in activation of cellular proliferation, differentiation and migration. Our preliminary data suggest that the expression of BRK/Sik is decreased during progression of oral SCC. We have available a large series of archived oral epithelia samples obtained from subjects whose subsequent clinical outcomes were monitored longitudinally. We hypothesize that presumed benign lesions with a low ratio of expression of BRK/Sik to its substrate SAM68 progress to dysplasia and to oral squamous cell carcinoma. Furthermore, subcellular localization of BRK/Sik may indicate the extent of epithelial proliferative capacity and thus development of oral cancer. We therefore expect to observe changes in BRK/Sik and SAM68 expression and subcellular localization in the early stages of premalignant lesions which develop into malignancy but not lesions which have not or will not reach this potential. The immediate goal of this project is to demonstrate that the pattern of BRK/Sik expression (determined by tissue microarray and Western blot analyses) can be used to determine the potential of leukoplakia to become malignant as suggested by our preliminary data. If a strong correlation exists between changes in BRK/Sik expression and subsequent development of malignancy, then a follow up study to demonstrate an altered pattern of BRK/Sik expression in clinical samples obtained by non-invasive brush biopsy will be undertaken. The long-term goal is the development of a non-invasive screening test to detect premalignant lesions and thus potential malignancy in oral SCC.